Disruptive polymer micelle composition

ABSTRACT

A pharmaceutical composition containing a drug encapsulated in a polymer micelle composition containing a first block copolymer having affinity with HDL and a second block copolymer having affinity with a lipoprotein excluding HDL, each block copolymer having a hydrophobic polymer chain segment and a hydrophilic polymer chain segment such that a plurality of block copolymers arrange radially with the hydrophobic segments directed inward and the hydrophilic segments directed outward. In the composition, a detachment of the first block copolymer is induced by HDL adhesion which forms a gap and promotes the release of a drug encapsulated, while the second block copolymer excluding an affinity with HDL controls a release speed of the drug encapsulated.

TECHNICAL FIELD

The present invention relates to a polymer micelle composition and apharmaceutical composition using the polymer micelle composition.

BACKGROUND ART

There are known a use of block copolymers each having a hydrophilicpolymer chain segment and a hydrophobic polymer chain segment as acarrier for drugs and a method encapsulating a predetermined drug into apolymer micelle formed of the copolymers (for example, Patent Document 1or 2). There are also known a composition including a homogeneouspolymer micelle encapsulating a poorly water-soluble drug and apreparation method therefor (Patent Document 3).

Patent Document 1 or 2 describes a method encapsulating a drug into amicelle preliminarily formed from block copolymers in an aqueous mediumby adding the drug to the micelle solution, and optionally, mixing andstirring the resultant under heating and ultrasonication. Further,Patent Document 3 describes a method for preparing a polymer micelleencapsulating a drug by dissolving block copolymers and drugs in awater-miscible polar solvent and then subjecting the resultant todialysis against water.

According to those prior arts, it is understood that the use of thepolymer micelle as the carrier for drugs has various advantagesincluding a sustained release of drug. However, in a conventionalpolymer micelle, a drug is encapsulated into the micelle in a verystable manner, which may inhibit the drug from being released suitably.

PRIOR ART DOCUMENTS Patent Document

-   [Patent Document 1] JP 06-107565 A-   [Patent Document 2] U.S. Pat. No. 5,449,513 A-   [Patent Document 3] JP 11-335267 A

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

A main object of the present invention is to provide a polymer micellecomposition capable of stably encapsulating and suitably releasing adrug, and a pharmaceutical composition using the polymer micellecomposition.

Means for Solving the Problems

The present invention provides a polymer micelle composition. Thepolymer micelle composition comprises block copolymers each having ahydrophobic polymer chain segment and a hydrophilic polymer chainsegment. A plurality of the block copolymers is arranged radially in astate in which the hydrophobic polymer chain segment is directed inwardand the hydrophilic polymer chain segment is directed outward. Thepolymer micelle composition comprises as the block copolymers, a blockcopolymer having affinity with HDL and a block copolymer having affinitywith a lipoprotein excluding HDL. The block copolymer having affinitywith HDL has a hydrophobic polymer chain segment formed of a polyaminoacid including repeating units derived from a hydrophobic derivative ofan amino acid. The hydrophobic derivative of an amino acid includes aderivative obtained by introducing an aromatic group and/or a sterolresidue into a side chain of the amino acid. The block copolymer havingaffinity with a lipoprotein excluding HDL has a hydrophobic polymerchain segment formed of a polyamino acid including repeating unitsderived from a hydrophobic derivative of an amino acid. The hydrophobicderivative of an amino acid includes a derivative obtained byintroducing a hydrophobic group having a linear or branched structureinto a side chain of the amino acid. A detachment of the block copolymerhaving affinity with HDL is induced by HDL adhesion attributed to theaffinity. A gap in polymer micelle produced through the detachmentcauses promotion of release of a drug to be encapsulated, i.e., one kindselected from the group consisting of water-soluble physiologicallyactive polypeptides and proteins each having a molecular weight of 1,500or more. The block copolymer having affinity with a lipoproteinexcluding HDL makes the gap smaller to suppress promotion of release ofthe drug to be encapsulated, which allows control of a release speed ofthe drug.

The present invention provides another polymer micelle composition inother aspect. The polymer micelle composition comprises block copolymerseach having a hydrophobic polymer chain segment and a hydrophilicpolymer chain segment. A plurality of the block copolymers is arrangedradially in a state in which the hydrophobic polymer chain segment isdirected inward and the hydrophilic polymer chain segment is directedoutward. The polymer micelle composition comprises a block copolymerhaving affinity with HDL as one of the block copolymers. The blockcopolymer having affinity with HDL has a hydrophobic polymer chainsegment formed of a polyamino acid including repeating units derivedfrom a hydrophobic derivative of an amino acid. The hydrophobicderivative of an amino acid includes a derivative obtained byintroducing a sterol residue into a side chain of the amino acid. Theblock copolymer having affinity with HDL has a hydrophilic polymer chainsegment of poly(ethylene glycol). A detachment of the block copolymerhaving affinity with HDL is induced by HDL adhesion attributed to theaffinity. A gap in the polymer micelle formed through the detachmentcauses promotion of release of a drug to be encapsulated, i.e., one kindselected from the group consisting of water-soluble physiologicallyactive polypeptides and proteins each having a molecular weight of 1,500or more.

The present invention provides a pharmaceutical composition in yetanother aspect. The pharmaceutical composition comprises above mentionedpolymer micelle composition and a drug encapsulated in the polymermicelle composition, i.e., one kind selected from the group consistingof water-soluble physiologically active polypeptides and proteins eachhaving a molecular weight of 1,500 or more.

Advantageous Effects of the Invention

According to the present invention, there can be provided the polymermicelle composition capable of stably encapsulating and suitablyreleasing a drug, and the pharmaceutical composition using the polymermicelle composition.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 are conceptual diagrams illustrating interactions between apolymer micelle composition of the present invention and lipoproteins.

FIG. 2 is a graph illustrating ratios of polymer contents in therespective lipoprotein fractions.

FIG. 3 is a graph illustrating the time-courses of plasma G-CSFconcentration in Example 1.

FIG. 4 is a graph illustrating the time-courses of plasma G-CSFconcentration in Example 4.

DESCRIPTION OF THE EMBODIMENTS

A. Polymer Micelle Composition

A polymer micelle composition of the present invention includes blockcopolymers each having a hydrophobic polymer chain segment and ahydrophilic polymer chain segment. A plurality of the block copolymersare arranged radially in a state in which the hydrophobic polymer chainsegment is directed inward and the hydrophilic polymer chain segment isdirected outward. The polymer micelle composition includes a blockcopolymer having affinity with high-density lipoprotein (HDL)(hereinafter, sometimes referred to as “block copolymer with HDLaffinity”) as one of the block copolymers. According to the polymermicelle composition, the detachment of the block copolymer with HDLaffinity is induced by HDL adhesion attributed to the affinity, and agap formed through the detachment causes the promotion of the release ofa drug to be encapsulated. The adhesion property of the polymericmicelle to HDL may be confirmed by observing the presence of blockcopolymers in an HDL fraction in the case of incubating the polymermicelle composition in the presence of HDL (for example, in plasma) andthen purifying the HDL fraction. The “hydrophobic polymer chain segment”and the “hydrophilic polymer chain segment” may have any suitablehydrophobic degree and hydrophilic degree, respectively, as long as amicelle in which a plurality of block copolymers each having those twosegments are arranged in the above-mentioned state can be formed in anaqueous medium.

A possible reason why the release of a drug from the polymer micellecomposition is promoted is as described below. As illustrated in FIG.1(A), in blood, HDL 20, which has an average particle diameter as smallas about 10 nm, can easily enter the interior (hydrophobic polymer chainsegment region) of a polymer micelle including block copolymers with HDLaffinity 10 each having a hydrophilic polymer chain segment 11 and ahydrophobic polymer chain segment 12. Each of the block copolymers withHDL affinity 10 interacts with HDL 20, which has entered the hydrophobicpolymer chain segment region, based on the HDL affinity, and ispreferentially detached from the polymer micelle through the adhesion ofHDL 20. As a result, gaps are formed in a polymer micelle structure,which facilitates the release of encapsulated drug 50. Further, thedisintegration of the polymer micelle easily occurs, which promotes therelease of the drug 50. Meanwhile, as illustrated in FIG. 1(B),low-density lipoprotein (LDL) 30, which has an average particle diameteras relatively large as about 26 nm, and very-low-density lipoprotein(VLDL) 40, which has a particle diameter equal to or more than thediameter of the LDL, are hard to enter the interior of the polymermicelle. Thus, when the fact that the block copolymers with HDL affinity10 inherently have weak interactions with those lipoproteins excludingHDL is also taken into consideration, the detachment of the blockcopolymers from the polymer micelle to be induced by the adhesion of alipoprotein excluding HDL should hardly occur.

As the drug to be encapsulated in the polymer micelle composition, onekind selected from the group consisting of water-soluble physiologicallyactive polypeptides and proteins each having a molecular weight of 1,500or more is preferable. The drug has a relatively large size and hencehardly leaks from small gaps between block copolymers in a conventionaltype polymer micelle. Thus, the drug is not sufficiently released and iseliminated from the blood circulation together with the micelle in somecases. On the other hand, the polymer micelle composition according tothe present invention exerts sustained-release performance of a drugthrough micelle formation, while it is also excellent for use inpromoting the release of such drug having a relatively large size ascompared to the conventional type polymer micelle. Further, as describedlater, in the polymer micelle composition according to the presentinvention, a block copolymer having affinity with a lipoproteinexcluding HDL such as LDL or VLDL (hereinafter, sometimes referred to as“block copolymer without HDL affinity”) may also be further incorporatedto control the degree of the release of a drug.

The hydrophobic polymer chain segment in the block copolymer with HDLaffinity may be formed of a polyamino acid. The polyamino acid includesrepeating units derived from a hydrophobic derivative of an amino acidobtained by introducing a hydrophobic group having a cyclic structureinto a side chain of the amino acid. The hydrophobic derivative of anamino acid having a cyclic structure is preferably a hydrophobicderivative of an acidic amino acid such as aspartic acid and glutamicacid, and a hydrophobic group having a cyclic structure may beintroduced into a carboxyl group in a side chain of the acidic aminoacid.

The hydrophobic group having a cyclic structure may be a group having amonocyclic structure or a group having a polycyclic structure, and forexample, may be an aromatic group, an alicyclic group, or a sterolresidue. The hydrophobic group is preferably a C₄ to C₁₆ alkyl grouphaving a cyclic structure, a C₆ to C₂₀ aryl group, a C₇ to C₂₀ aralkylgroup, and a sterol residue. A sterol means a natural, semisynthetic, orsynthetic compound based on a cyclopentanone hydrophenanthrene ring(C₁₇H₂₈) and derivatives thereof. For example, a natural sterol isexemplified by cholesterol, cholestanol, dihydrocholesterol, cholicacid, campesterol, and sitosterol. The semisynthetic or syntheticcompounds may be, for example, synthetic precursors of the naturalsterol (as necessary, encompassing a compound in which part or all of,if present, certain functional groups, hydroxy groups have beenprotected with a hydroxy protective group known in the art, or acompound in which a carboxyl group has been protected with carboxylprotective group). The sterol derivative may have a C₆ to C₁₂ alkylgroup or a halogen atom such as chlorine, bromine, and fluorineintroduced into a cyclopentanone hydrophenanthrene ring as long as theobject of the present invention is not adversely affected. Thecyclopentanone hydrophenanthrene ring may be saturated or partiallyunsaturated.

The hydrophobic polymer chain segment in the block copolymer with HDLaffinity may have not only repeating units derived from a hydrophobicderivative of an amino acid having a cyclic structure but also otherrepeating units as long as the effects of the present invention areexerted. Examples of the other repeating units include: repeating unitsderived from an acidic amino acid such as glutamic acid and asparticacid, and for example, a hydrophobic derivative obtained by introducinga 0₄ to C₁₆ unsubstituted or substituted linear or branched alkyl groupinto the acidic amino acid.

The content of the repeating units derived from the hydrophobicderivative of an amino acid having a cyclic structure is preferably 10to 100 mol %, more preferably 20 to 80 mol % with respect to the total(100 mol %) of the repeating units for forming the hydrophobic polymerchain segment in the block copolymer with HDL affinity. Theabove-mentioned content can provide the affinity with HDL more surely.

Examples of the hydrophilic polymer chain segment in the block copolymerwith HDL affinity include poly (ethylene glycol), polysaccharide,poly(vinyl pyrrolidone), poly(vinyl alcohol), poly(acrylic amide),poly(acrylic acid), poly(methacrylic amide), poly(methacrylic acid),poly(methacrylic acid ester), poly(acrylic acid ester), polyamino acid,poly(malic acid), and derivatives thereof. Specific examples of thepolysaccharide include starch, dextran, fructan, and galactan.

In the block copolymer with HDL affinity, the hydrophilic polymer chainsegment and the hydrophobic polymer chain segment are linked to eachother through a known linking group. Examples of the linking groupinclude an ester bond, an amide bond, an imino group, a carbon-carbonbond, and an ether bond. The end opposite to the end at the side of thehydrophilic polymer chain segment in the hydrophobic polymer chainsegment and the end opposite to the end at the side of the hydrophobicpolymer chain segment in the hydrophilic polymer chain segment maybesubjected to any suitable chemical modification as long as the formationof a polymer micelle is not adversely affected.

The block copolymer with HDL affinity may have a hydrophilic polymerchain segment of poly(ethylene glycol) and a hydrophobic polymer chainsegment formed of a polyamino acid including repeating units derivedfrom a hydrophobic derivative of an amino acid. The hydrophobicderivative of an amino acid may be a derivative obtained by introducinga sterol residue into a side chain of the amino acid.

The block copolymer with HDL affinity maybe represented by each of thefollowing general formulae (I) and (II). The polymer micelle compositionof the present invention may include two or more kinds of blockcopolymers with HDL affinity.

In each of the above-mentioned formulae, R¹ and R³ each independentlyrepresent a hydrogen atom or a lower alkyl group substituted orunsubstituted by an optionally protected functional group;

-   R² represents a hydrogen atom, a saturated or unsaturated C₁ to C₂₉    aliphatic carbonyl group, or an arylcarbonyl group;-   R⁴ represents a hydroxyl group, a saturated or unsaturated C₁ to C₃₀    aliphatic oxy group, or an aryl-lower alkyloxy group;-   R⁵'s each represent —O— or —NH—;-   R⁶'s each represent a hydrogen atom, a C₄ to C₁₆ alkyl group having    a cyclic structure unsubstituted or substituted by an amino group or    a carboxyl group, a C₆ to C₂₀ aryl group, a C₇ to C₂₀ aralkyl group,    or a steryl group;-   R⁷ and R⁸ each independently represent a methylene group or an    ethylene group;-   n represents an integer in the range of 10 to 2,500;-   x represents an integer in the range of 10 to 300;-   m represents an integer in the range of 0 to 300 (provided that,    when m represents 1 or more, a repeating unit with the number of    repetitions of x and a repeating unit with the number of repetitions    of m are bound to each other in any suitable order, R⁶'s are each    independently selected in the respective repeating units in one    block copolymer and are present at random, and 10% or more of a    total of R⁶'s are each independently selected from a C₄ to C₁₆ alkyl    group having a cyclic structure unsubstituted or substituted by an    amino group or a carboxyl group, a C₆ to C₂₀ aryl group, a C₇ to C₂₀    aralkyl group, and a steryl group);-   L¹ represents a linking group selected from the group consisting of    —NH—, —O—, —O—Z—NH—, —CO—, —CH₂—, —O—Z—S—Z—, and —OCO—Z—NH— (where    Z's independently represent a C₁ to C₆ alkylene group); and-   L²represents a linking group selected from —OCO—Z—CO— and    —NHCO—Z—CO— (where Z represents a C₁ to C₆ alkylene group).

The C₆ to C₂₀ aryl group and the C₇ to C₂₀ aralkyl group are exemplifiedby preferably a phenyl group, a naphthyl group, a tolyl group, a xylylgroup, a benzyl group, and a phenethyl group, more preferably a benzylgroup. Further, a sterol from which the steryl group is derived isexemplified by preferably cholesterol, cholestanol, anddihydroxycholesterol, more preferably cholesterol.

n in each of the above-mentioned formulae represents an integer in therange of preferably 10 to 1,000, more preferably 20 to 600, particularlypreferably 50 to 500. x and m in each of the above-mentioned formulaeeach represent an integer in the range of preferably 20 to 200, morepreferably 30 to 100.

Examples of the optionally protected functional group include a hydroxylgroup, an acetal, a ketal, an aldehyde, a sugar residue, a maleimidegroup, a carboxyl group, an amino group, a thiol group, and an activeester. The hydrophilic polymer chain segment in the case where R¹ and R³each represent a lower alkyl group substituted by an optionallyprotected functional group may be prepared, for example, in accordancewith the methods described in WO 96/33233 A1, WO 96/32434 A1, and WO97/06202 A1. The lower alkyl group means a linear or branched alkylgroup having, for example, 7 or less, preferably 4 or less carbon atoms.

The block copolymer with HDL affinity may be obtained, for example, bycoupling a polymer having a hydrophilic polymer chain and a polymerhaving a polyamino acid chain by a known method, each of which has notbeen subjected to any treatment or has been purified so as to achievenarrow molecular weight distribution as necessary. The block copolymerof the general formula (I) may also be formed, for example, by carryingout anionic living polymerization using an initiator capable of givingR¹ to form a polyethylene glycol chain, then introducing an amino groupat the side of the growing end, and polymerizing an N-carboxylicanhydride (NCA) of a protected amino acid such as β-benzyl-L-aspartateor γ-benzyl-L-glutamate from the amino end.

A specific example of a method of manufacturing the block copolymer withHDL affinity is described below. (i) N-carboxy-β-benzyl-L-asparticanhydride (BLA-NCA) or (ii) N-carboxy-β-benzyl-L-glutamic anhydride(BLG-NCA) are added and subjected to a reaction using, as an initiator,polyethylene glycol, which is protected at one end and has an aminogroup at the other end, such as MeO—PEG-CH₂CH₂CH₂—NH₂, in a dehydrateorganic solvent so as to achieve a desired polymerization degree (numberof amino acid units), to thereby afford (i) polyethyleneglycol-co-polyaspartic acid benzyl ester or (ii) polyethyleneglycol-co-polyglutamic acid benzyl ester. In addition, the resultantblock copolymer is acetylated at the end with acetyl chloride or aceticanhydride, then subjected to alkali hydrolysis to remove a benzyl group,and converted into polyethylene glycol-co-polyaspartic acid orpolyethylene glycol-co-polyglutamic acid. After that, benzyl alcohol isadded in an organic solvent so as to achieve a desired esterificationratio, and a reaction is carried out in the presence of a condensationagent such as N-N′-dicyclohexyl carbodiimide (DCC) and N-N′-diisopropylcarbodiimide (DIPCI) to afford a block copolymer partially having abenzyl ester.

When a reaction is performed using cholesterol in place of benzylalcohol, polyethylene glycol-co-polyaspartic acid cholesterol ester andpolyethylene glycol-co-polyglutamic acid cholesterol ester may beprepared.

Another specific example of the method of manufacturing the blockcopolymer with HDL affinity is a method involving introducing ahydrophobic side chain through an amide bond. In the manufacturingmethod, polyethylene glycol-co-polyaspartic acid benzyl ester orpolyethylene glycol-co-polyglutamic acid benzyl ester is acetylated atthe end in the same manner as described above. Then, a benzyl group isremoved by alkali hydrolysis and the generated carboxyl group issubjected to a reaction with a hydrophobic side chain having an aminogroup. Alternatively, polyethylene glycol-co-polyaspartic acid benzylester or polyethylene glycol-co-polyglutamic acid benzyl ester and acompound having a primary amine are subjected to a reaction and thensubjected to aminolysis to convert an ester bond to an amide bond. Thisallows the introduction of a hydrophobic side chain through an amidebond. In addition, a poly(amino acid derivative) segment including ahydrophobic side chain having a hydrophobic group whose end has beensubstituted by an amino group and a hydrophobic side chain without aminogroup substitution may also be obtained by adding a primary amine suchas 1-octylamine to polyethylene glycol-co-polyaspartic acid benzyl esterin an organic solvent so as to achieve a desired amidation ratio,subjecting the mixture to a reaction for a predetermined period of time,and then adding a large excess amount of 1,8-diaminooctane or the liketo an unconverted benzyl ester.

The block copolymer with HDL affinity has an HDL transfer rate, which isdetermined as described below, of 30% or more owing to its affinity withHDL. The block copolymer with HDL affinity has an HDL transfer rate ofpreferably 40% or more, more preferably 45% or more, particularlypreferably 50% or more.

[Method of Determining HDL Transfer Rate]

Block copolymers are used as a polymer micelles encapsulating lysozyme,and the polymer micelles are incubated in plasma at 37° C. for 24 hours.After that, the respective lipoprotein fractions are purified andcollected. The concentration of the block copolymers in each of thecollected VLDL, LDL, HDL, and residual fractions is measured. Then, thecontent (on the weight basis) of the block copolymers in each of thefractions is calculated based on the volume and block copolymerconcentration in each of the fractions. The resultant value issubstituted for the following equation to determine an HDL transferrate.

HDL transfer rate (%)=Block copolymer content in HDL fraction/Total ofblock copolymer contents in respective fractions×100

In determining the HDL transfer rate, the block copolymer with HDLaffinity is preferably present in an HDL fraction in the highest amountamong other lipoprotein fractions (excluding a chylomicron fraction).That is, it is preferred that the content of the block copolymer withHDL affinity in the HDL fraction be highest among the contents of theblock copolymer with HDL affinity in the respective fractions, i.e.,VLDL, LDL, HDL, and residual fractions.

The polymer micelle composition may further include a block copolymerwithout HDL affinity as one of the block copolymers each having ahydrophobic polymer chain segment and a hydrophilic polymer chainsegment. It is difficult to detach the block copolymer without HDLaffinity preferentially from the polymer micelle. This is because anentry into the interior of the polymer micelle is difficult forlipoproteins except HDL. Thus, when the polymer micelle composition isprepared as a mixed type of a block copolymer with HDL affinity and ablock copolymer without HDL affinity, gap formation due to thedetachment of the block copolymers with HDL affinity may be suppressed,and in some cases, gap formation may be promoted owing to a reduction inhydrophobic interaction between the block copolymers for forming thepolymer micelle composition on the contrary. As described above, therelease speed of a drug from the polymer micelle composition may becontrolled by adjusting the contents of the block copolymer with HDLaffinity and the block copolymer without HDL affinity. That is,according to the present invention, there can be provided a polymermicelle having disruptive property, which has been conventionallydifficult to be imparted, and further, the control of the disintegrationspeed of the polymer micelle can also be facilitated.

The hydrophobic polymer chain segment in the block copolymer without HDLaffinity may be formed of a polyamino acid including repeating unitsderived from a hydrophobic derivative of an amino acid obtained byintroducing a hydrophobic group having a linear or branched structureinto a side chain of the amino acid. The hydrophobic derivative of anamino acid is a hydrophobic derivative of preferably an acidic aminoacid, more preferably aspartic acid and/or glutamic acid.

The hydrophobic group having a linear or branched structure isexemplified by a C₄ to C₁₈ unsubstituted or substituted linear orbranched alkyl group, a C₄ to C₁₈ unsubstituted or substituted linear orbranched alkenyl group, and a C₄ to C₁₈ unsubstituted or substitutedlinear or branched alkynyl group, preferably a C₄ to C₁₈ unsubstitutedor substituted linear or branched alkyl group.

As for the hydrophilic polymer chain segment in the block copolymerwithout HDL affinity, the same hydrophilic polymer as in the case withthe hydrophilic polymer chain segment in the block copolymer with HDLaffinity may be selected. Further, the end modification of each of thehydrophilic polymer chain segment and the hydrophobic polymer chainsegment in the block copolymer without HDL affinity and the linking ofthose segments are also as described in the paragraph relating to theblock copolymer with HDL affinity.

The block copolymer without HDL affinity may be represented by each ofthe following general formulae (III) and (IV):

In each of the above-mentioned formulae, R⁹ and R¹¹ each independentlyrepresent a hydrogen atom or a lower alkyl group substituted orunsubstituted by an optionally protected functional group;

-   R¹⁰ represents a hydrogen atom, a saturated or unsaturated C₁ to C₂₉    aliphatic carbonyl group, or an arylcarbonyl group;-   R¹² represents a hydroxyl group, a saturated or unsaturated C₁ to    C₃₀ aliphatic oxy group, or an aryl-lower alkyloxy group;-   R¹³'s each represent —O— or —NH—;-   R¹⁴'s each represent a hydrogen atom, a C₄ to C₁₈ linear or branched    alkyl group unsubstituted or substituted by an amino group or a    carboxyl group;-   R¹⁵ and R¹⁶ each independently represent a methylene group or an    ethylene group;-   p represents an integer in the range of 10 to 2,500;-   q represents an integer in the range of 10 to 300;-   r represents an integer in the range of 0 to 300 (provided that,    when r represents 1 or more, a repeating unit with the number of    repetitions of q and a repeating unit with the number of repetitions    of r are bound to each other in any suitable order, R¹⁴'s are each    independently selected in the respective repeating units in one    block copolymer and are present at random, and 40% or less of a    total of R¹⁴'s are hydrogen atom);-   L³ represents a linking group selected from the group consisting of    —NH—, —O—, —O—Z—NH—, —CO—, —CH₂, —O—Z—S—Z—, and —OCO—Z—NH— (where    Z's independently represent a C₁ to C₆ alkylene group); and-   L⁴ represents a linking group selected from —OCO—Z—CO— and    —NHCO—Z—CO— (where Z represents a C₁ to C₆ alkylene group).

p in each of the above-mentioned formulae represents an integer in therange of preferably 10 to 1,000, more preferably 20 to 600, particularlypreferably 50 to 500. q and r in each of the above-mentioned formulaeeach represent an integer in the range of preferably 20 to 200, morepreferably 30 to 100.

The optionally protected functional group is as described in theparagraph relating to each of the formulae (I) and (II).

The HDL transfer rate of the block copolymer without HDL affinity may beless than 30%, preferably 25% or less, more preferably 20% or less.

The content ratio of the block copolymer with HDL affinity to the blockcopolymer without HDL affinity in the polymer micelle composition of thepresent invention (block copolymer with HDL affinity:block copolymerwithout HDL affinity, weight ratio) may be set depending on the intendeduse of the polymer micelle composition, the HDL transfer rate of each ofthe block copolymers, and the like. The content ratio (block copolymerwith HDL affinity:block copolymer without HDL affinity, weight ratio)may be, for example, in the range of 1:99 to 99:1, in the range of 3:97to 97:3, in the range of 15:85 to 85:15, or in the range of 40:60 to60:40. As described above, the weight ratio of the block copolymer withHDL affinity with respect to the total weight of the block copolymerwith HDL affinity and the block copolymer without HDL affinity in thepolymer micelle composition may be, for example, 60% or less, 50% orless, 40% or less, 20% or less, 10% or less, 5% or less, 2% or less, or1% or less. There is a tendency that the disintegration of the polymermicelle is induced to promote the release of a drug when the contentratio of the block copolymer with HDL affinity is large. Meanwhile,there is a tendency that the disintegration of the polymer micelle andthe attendant release of a drug are suppressed when the content ratio ofthe block copolymer with HDL affinity is small.

B. Pharmaceutical Composition

A pharmaceutical composition of the present invention includes thepolymer micelle composition described in the above-mentioned section Aand a drug encapsulated in the polymer micelle composition. The drug isdesirably one kind selected from the group consisting of water-solublephysiologically active polypeptides and proteins. In addition, the drughas a molecular weight of desirably 1,500 or more, preferably 2,000 ormore. Preferred examples of the physiologically active polypeptides andproteins include: interferons α, β, and γ; erythropoietin; G-CSF; growthhormone; interleukins; tumor necrosis factor; granulocyte-macrophagecolony-stimulating factor; macrophage colony-stimulating factor;hepatocyte growth factor; TGF-β superfamily; EGF; FGF; IGF-I; and bloodcoagulation factors typified by Factor VII. Further, as long as theactivities are not impaired, derivatives of the above-mentionedproteins, more specifically, proteins having substitutions, additions,or deletions in one or more amino acids may be used as medicaments.

The drug may be a poorly water-soluble drug having a water solubility of100 μg/mL or less. Examples of the poorly water-soluble drug include:anti-cancer agents such as paclitaxel, topotecan, camptothecin,cisplatin, daunorubicin hydrochloride, methotrexate, mitomycin C,docetaxel, vincristine sulfate, and derivatives thereof; polyene-basedantibiotics such as amphotericin B and nystatin; and lipophilic drugssuch as prostaglandins and derivatives thereof. The poorly water-solubledrug has a relatively small size but may be difficult to be releasedfrom a conventional type polymer micelle composition owing to its highhydrophobicity. On the other hand, the pharmaceutical composition of thepresent invention is also excellent for use in promoting the release ofsuch poorly water-soluble drug as compared to the conventional typepolymer micelle composition.

The amount of the drug to be encapsulated may be set depending on theintended use of the pharmaceutical composition and the like. The amountof the drug to be used is generally 0.01 to 50 wt %, preferably 0.1 to10 wt % with respect to the total of the block copolymers in the polymermicelle composition.

The particle diameter of the polymer micelle encapsulating a drug is notparticularly limited as long as it is a size capable of beingadministered to a living body. The particle diameter is preferably 10 μmor less, more preferably 5 μm or less. In particular, when the polymermicelle is used in intravenous administration, the particle diameter ispreferably 500 nm or less, more preferably 300 nm or less.

The pharmaceutical composition may be prepared as described below, forexample. First, the above-mentioned block copolymers are dissolved in anorganic solvent. As necessary, the organic solvent may be removed bysubjecting the resultant solution to air drying, e.g., drying to form afilm under a nitrogen gas stream atmosphere and further drying underreduced pressure as necessary. To the block copolymers thus treated wasadded and mixed a solution containing a drug to be encapsulated. Then, apolymer micelle is formed from the resultant mixed solution while thedrug is encapsulated.

Examples of the organic solvent include: non-water-miscible organicsolvents such as dichloromethane, chloroform, diethyl ether, dibutylether, ethyl acetate, and butyl acetate; water-miscible organic solventssuch as methanol, ethanol, propyl alcohol, isopropyl alcohol,dimethylsulfoxide, dimethylformamide, dimethylacetamide, acetonitrile,acetone, and tetrahydrofuran; and mixed solvents thereof.

The polymer micelle encapsulating a drug may be formed, for example, bystirring a mixed solution of block copolymers and a drug while applyingthe solution with energy by ultrasonic irradiation. The ultrasonicirradiation may be performed, for example, using a biodisruptor(manufactured by NIHONSEIKI KAISHA LTD.).

C. Method of Controlling Release Speed of Drug from PharmaceuticalComposition

The method involves changing the content ratio of the block copolymerwith HDL affinity with respect to the total of the block copolymers inthe polymer micelle composition in the pharmaceutical compositiondescribed in the above-mentioned section B. The block copolymer with HDLaffinity is capable of exerting an effect of promoting the release of adrug from a polymer micelle. Thus, the content ratio of the blockcopolymer with HDL affinity may be changed to control the release speedof a drug from a polymer micelle.

For example, the content ratio of the block copolymer with HDL affinitywith respect to the total of the block copolymers in the polymer micellecomposition (content of block copolymer with HDL affinity/total ofcontents of block copolymers, weight ratio) is set in the range of morethan 0/100 to 100/100 or less, preferably 1/100 to 100/100. Morespecifically, the content ratio of the block copolymer with HDL affinitywith respect to the block copolymer without HDL affinity in the polymermicelle composition (block copolymer with HDL affinity:block copolymerwithout HDL affinity, weight ratio) is set, for example, in the range of1:99 to 99:1, in the range of 3:97 to 97:3, in the range of 15:85 to85:15, or in the range of 40:60 to 60:40. There is a tendency that therelease of a drug may be promoted when the content ratio of the blockcopolymer with HDL affinity is large, whereas the release of a drug maybe suppressed when the content ratio is small.

EXAMPLES

In the following description, for the purpose of simplified expression,for example, when a block copolymer has a hydrophilic polymer chainsegment formed of a PEG chain having an average molecular weight of10,000 and a hydrophobic polymer chain segment formed of a polyaminoacid chain having 40 amino acid residues on average, and has anintroduction rate of a benzyl group into a side chain of the polyaminoacid chain of about 65%, the expression “block copolymer (10-40, 65%Bn)” is used. Similarly, when hydrophobic groups to be introduced into aside chain of the polyamino acid chain are an octyl group and acholesteryl group, the expressions “block copolymer (10-40, 65% C8)” and“block copolymer (10-40, 65% Chol)” are used, respectively. Theintroduction rate of a hydrophobic group of about 65% includes 62 to68%.

Reference Example 1 Preparation of Polymer Micelle EncapsulatingLysozyme

The block copolymers described in the following general formula (V) andTable 1 were used as block copolymers. Each of the block copolymers wasweighed in a vial and purified water was added thereto so as to achievea polymer concentration of 5 mg/mL. Then, the polymer solutions werevigorously stirred at 4° C. overnight. The polymer solutions weresubjected to ultrasonic irradiation (in an ice water bath, Low, intervalof 1 second, 10 minutes) using a biodisruptor (High Power Unitmanufactured by NIHONSEIKI KAISHA LTD.) and then treated with a 0.22-μmmembrane filter. Thus, empty micelle solutions each having a polymerconcentration of 5 mg/mL are obtained. To each of the empty micellesolutions (0.6 mL) were added al mg/mL lysozyme solution (0.15 mL) so asto achieve a concentration of 5% (w/w) with respect to the polymer, a200 mM sodium phosphate buffer (pH 6), and purified water. The resultantmixtures were adjusted with 0.1 N HCl so as to finally achieve a polymerconcentration of 3 mg/mL, a lysozyme concentration of 0.15 mg/mL, and acomposition of a 20 mM sodium phosphate buffer as well as a pH of 6. Thesolutions were inverted and swirled two or three times and then left tostand still at 4° C. overnight. The micelles each encapsulating lysozymeprepared as described above were warmed to room temperature, and thenthey were used.

In the above-mentioned formula, a glutamic acid unit and its hydrophobicderivative unit are bound to each other in any suitable order and arepresent at random in one block copolymer.

TABLE 1 PEG molecular Block copolymer weight R₁₇ t PEG-pGlu (10-40, 60%Bn) 10,000 Benzyl group 24 PEG-pGlu (10-40, 30% Chol) 10,000 Cholesterylgroup 12 PEG-pGlu (10-40, 60% C8) 10,000 Octyl group 24 PEG-pGlu (10-40,60% C12) 10,000 Dodecyl group 24 PEG-pGlu (10-40, 60% C16) 10,000Hexadecyl group 24

Reference Example 2 HDL Transfer Rate

The polymer micelles each encapsulating lysozyme prepared in ReferenceExample 1 were used to determine an HDL transfer rate of each of theblock copolymers. A specific experimental method is described below. To810 μL of rat plasma stored at −80° C. after the centrifugation of bloodcollected with heparin from each of 8-week-old male Wistar rats wereadded 90 μL each of the polymer micelles each encapsulating lysozyme,and the mixture was incubated at 37° C. for 24 hours (final lysozymeconcentration: 15 μg/mL, final polymer concentration: 300 μg/mL). Themixture was then subjected to ultracentrifugation under the conditionsof 45,000 rpm (about 100,000 g), 15 minutes, and 4° C. (Rotar: MLA-130,Centrifuge tube: thick-walled polyallomer tube) using an “OptimaMAX”(trade name) (manufactured by Beckman) in accordance with the protocolof Axis-Shield Density Gradient Media downloadable fromhttp://www.axis-shield-density-gradient-media.com/CD2009/macromol/M07.pdf. Then, a chylomicron fraction as the uppermost layer wasremoved from the plasma after ultracentrifugation. After that, 180 μL ofan “Optiprep (registered trademark)” (trade name) (manufactured byAxis-shield) in a ¼ volume of the plasma were added and mixed withrespect to 720 μL of the plasma, and the mixture was subjected toultracentrifugation under the conditions of 85,000 rpm (about 350,000g), 3 hours, and 16° C. During the ultracentrifugation, balanceadjustment was carried out using a 0.85% (w/v) NaCl/10 mM2-[4-(2-hydroxyethyl)-1-piperazinyl]-ethanesulfonic acid (HEPES) buffer(pH 7.4). After the ultracentrifugation, VLDL, LDL, HDL, and residual(other) fractions were collected and the block copolymer concentrationin each of the fractions was measured using a PEG-ELISA kit(manufactured by Life Diagnostics). Based on the resultant polymerconcentration and the volume of each of the fractions, the content ofthe block copolymer in each of the fractions and its ratio (i.e.,transfer rate of block copolymer to each fraction) were calculated. FIG.2 shows the results.

As seen from FIG. 2, both of PEG-pGlu (10-40, 60% Bn) and PEG-pGlu(10-40, 30% Chol) had an HDL transfer rate of 50% or more and showedhigh HDL affinity. On the other hand, all of PEG-pGlu (10-40, 60% C8),PEG-pGlu (10-40, 60% C12), and PEG-pGlu (10-40, 60% C16) had an HDLtransfer rate of less than 20% and showed higher affinity with otherlipoproteins such as LDL and VLDL than HDL.

Example 1 Rat Intravenous Administration Test of Polymer MicelleEncapsulating G-CSF (1) PEG-pGlu (10-40, 30% Chol)

PEG-pGlu (10-40, 30% Chol) was used as a block copolymer. The blockcopolymer was weighed in a vial. A 20 mM 2-morpholino ethanesulfonicacid monohydrate (MES) buffer (pH 5) was added thereto so as to achievea polymer concentration of 2 mg/mL and the mixture was vigorouslystirred at 4° C. overnight. The polymer solution was subjected toultrasonic irradiation (in an ice water bath, Low, interval of 1 second,10 minutes) using a biodisruptor (High Power Unit manufactured byNIHONSEIKI KAISHA LTD.) and then treated with a 0.22-μm membrane filter.Thus, an empty micelle solution having a polymer concentration of 2mg/mL was obtained. To the resultant empty micelle solution (6 mL) wasadded a 300 μg/mL G-CSF solution (2 mL) so as to achieve a concentrationof 5% (w/w) with respect to the polymer and the mixture was inverted andswirled and then left to stand still at 4° C. overnight. After that, thesolution was purified and concentrated by ultrafiltration using an“Amicon Ultra (registered trademark)” (trade name) (manufactured byMillipore Corporation, cutoff molecular weight: 100,000), and the mediumwas replaced by a 10% (w/w) sucrose aqueous solution. The collectedpolymer micelle encapsulating G-CSF was stored at −80° C. and thawed atroom temperature before use.

The solution of the polymer micelle encapsulating G-CSF obtained abovewas administered to male Wistar rats via the tail vein. The dosage was100 μg/kg of body weight and the number of animals for the sample wasthree. Blood was collected with a heparin-treated syringe from thejugular vein under ether anesthesia 5 minutes, 1 hour, 6 hours, 1 day, 2days, and 3 days after the administration. The plasma G-CSFconcentration was measured using a G-CSF-ELISA kit (manufactured byRayBiotech, Inc.).

(2) PEG-pGlu (10-40, 60% C8)

A polymer micelle encapsulating G-CSF was prepared in the same manner asin the test example using PEG-pGlu (10-40, 30% Chol) except thatPEG-pGlu (10-40, 60% C8) was used as the block copolymer and the numberof animals for the sample was nine. The time-courses of plasma G-CSFconcentration were examined.

(3) Mixed Polymer Micelle

PEG-pGlu (10-40, 30% Chol) and PEG-pGlu (10-40, 60% C8) were eachweighed in an equal amount and both of the polymers were dissolved indichloromethane and completely homogenized. After that, the solvent wasremoved using a shaking concentrator to produce a film. An empty micellewas then obtained in accordance with a conventional method. G-CSF wasthen encapsulated into the empty micelle so as to achieve aconcentration of 5% (w/w) with respect to the polymers in accordancewith a conventional method. The resultant polymer micelle encapsulatingG-CSF was administered to rats to examine the time-courses of plasmaG-CSF concentration.

(4) Direct Administration of G-CSF

The time-courses of plasma G-CSF concentration was examined in the samemanner as in the test example using PEG-pGlu (10-40, 30% Chol) exceptthat a G-CSF solution (100 μg/mL) was used in place of the solution ofthe polymer micelle encapsulating G-CSF and the number of animals forthe sample was five.

FIG. 3 illustrates the results of Example 1 (average±SD). FIG. 3 alsoillustrates theoretical values for time-courses of plasma concentrationof a mixed polymer micelle (1:1), which are calculated from the resultsof time-courses of plasma concentration of the test examples usingPEG-pGlu (10-40, 30% Chol) and PEG-pGlu (10-40, 60% C8).

As illustrated in FIG. 3, when G-CSF was directly administered, G-CSFwas degraded or metabolized very rapidly and the retention time inplasma was extremely short. On the other hand, when G-CSF encapsulatedin polymer micelles was administered, the retention time in plasma wasgreatly prolonged. In addition, the polymermicelle formed of a blockcopolymer with HDL affinity promoted the release of G-CSF as compared tothe polymer micelle formed of a block copolymer without HDL affinity.Further, in the mixed polymer micelle including PEG-pGlu (10-40, 30%Chol) and PEG-pGlu (10-40, 60% C8) at 1:1, observed values for theplasma G-CSF concentration were markedly lower than theoretical valuestherefor. This revealed that a mixture of a plurality of blockcopolymers different from each other in affinity with a lipoprotein gavea surprising drug release promoting action unexpected from its polymermixed ratio.

Example 2 (1) C8-Type Micelle

PEG-pGlu (10-40, 90% C8) was used as a block copolymer. The blockcopolymer was weighed in a vial. A 20 mM MES Buffer (pH 5) including13.3% sucrose was added thereto so as to achieve a polymer concentrationof 10 mg/mL, and the mixture was vigorously stirred at 4° C. overnight.The polymer solution was subjected to ultrasonic irradiation (in an icewater bath, High, interval of 1 second, 15 minutes×3) using abiodisruptor (NIHONSEIKI KAISHA LTD., High Power Unit) and then treatedwith a 0.22-μm membrane filter. To the solution was added theabove-mentioned 20 mM MES Buffer (pH 5) including sucrose and thepolymer concentration was adjusted to 2 mg/mL to obtain an empty micellesolution. To the resultant empty micelle solution (1.2 mL) was added a300 μg/mL G-CSF solution (0.4 mL) so as to achieve a concentration of 5%(w/w) with respect to the polymer, and the mixture was inverted andswirled, left to stand still at 4° C. overnight, and then stored at −80°C. The stored mixture was thawed at room temperature before use.

(2) Bn-Type Micelle

A polymer micelle encapsulating G-CSF was prepared in the same manner asin the test example of the C8-type micelle except that PEG-pGlu (10-40,100% Bn) was used as the block copolymer.

(3) Mixed-Type Micelle

PEG-pGlu (10-40, 90% C8) and PEG-pGlu (10-40, 100% Bn) were each weighedin a vial and completely dissolved with acetone so as to achieve apolymer concentration of 10 mg/mL. The solutions were mixed with eachother so that the weight ratios of PEG-pGlu (10-40, 90% C8) to PEG-pGlu(10-40, 100% En) were 19:1, 4:1, and 1:1. After that, the solvent wasremovedusing a shaking concentrator to produce a film. Then, an emptymicelle was obtained in accordance with a conventional method. Then,G-CSF was encapsulated into the empty micelle so as to achieve aconcentration of 5% (w/w) with respect to the polymers in accordancewith a conventional method.

Those solutions of the polymer micelles each encapsulating G-CSF wereadministered to male Wistar rats (6-week-old) via the tail vein underlight ether anesthesia. The dosage was 100 μg/kg of body weight and thenumber of animals for the sample was three for each solution. Blood wascollected with a heparin-treated syringe 24 hours after theadministration, and EDTA-2Na was added so that the final concentrationwas 1 mg/ml. In this state, the number of neutrophils was measured usinga multiple automated hematology analyzer for veterinary use (pocH-100iVDiff manufactured by SYSMEX CORPORATION). Based on the resultantmeasured values, drug release coefficients (%) of the Bn-type micelleand various mixed-type micelles were calculated in accordance with thefollowing equation. Table 2 shows the calculated drug releasecoefficients of the polymer micelles. It is conceivable that the largercoefficient should mean that the polymer micelle has a stronger actionof actively releasing a drug than the C8-type micelle.

Drug release coefficient (%)=100×(A−B)/(A−C)

-   A: Number of neutrophils in the animals to which C8-type micelle was    administered-   B: Number of neutrophils in the animals to which each of various    mixed-type micelles was administered-   C: Number of neutrophils in untreated animals

TABLE 2 Drug release coefficient Bn-type micelle 30% Mixed-type micelle(C8:Bn = 1:1) 20% Mixed-type micelle (C8:Bn = 4:1) 15% Mixed-typemicelle (C8:Bn = 19:1) 19%

As described above, also in the case where a benzyl type polymer wasselected as the block copolymer with HDL affinity, the release speed ofa drug can be controlled by employing a mixed-type micelle.

Example 3 (1) C8-Type Micelle

A polymer micelle encapsulating G-CSF was prepared in the same manner asin the test example of the C8-type micelle of Example 2.

(2) Chol-Type Micelle

A polymer micelle encapsulating G-CSF was prepared in the same manner asin the test example of PEG-pGlu (10-40, 30% Chol) except that PEG-pGlu(10-40, 25% Chol) was used as the block copolymer.

(3) Mixed-Type Micelle

G-CSF was encapsulated in an empty micelle in the same manner as inExample 2 except that: PEG-pGlu (10-40, 25% Chol) was used in place ofPEG-pGlu (10-40, 100% Bn); dichloromethane was used as the solvent fordissolving PEG-pGlu (10-40, 90% C8) ; and PEG-pGlu (10-40, 90% C8) andPEG-pGlu (10-40, 25% Chol) were mixed with each other at weight ratiosof 19:1 and 4:1.

The number of neutrophils was measured in the same manner as in Example2 except that the number of animals for the sample was six. Based on theresultant measured values, drug release coefficients (%) of theChol-type micelle and various mixed-type micelles were calculated in thesame manner as in Example 2. Table 3 shows the calculated drug releasecoefficients of the polymer micelles.

TABLE 3 Drug release coefficient Chol-type micelle 55% Mixed-typemicelle (C8:Chol = 4:1) 51% Mixed-type micelle (C8:Chol = 19:1) 26%

As described above, also in the case where a cholesterol type polymerwas selected as the block copolymer with HDL affinity, the release speedof a drug can be controlled by employing a mixed-type micelle.

Example 4 Rat Intravenous Administration Test of Polymer MicelleEncapsulating G-CSF (1) C8-Type Micelle

A polymer micelle encapsulating G-CSF was prepared in the same manner asin the test example of the C8-type micelle of Example 2.

(2) Chol-Type Micelle

A polymer micelle encapsulating G-CSF was prepared in the same manner asin the test example of the Chol-type micelle of Example 3.

(3) Mixed Polymer Micelle

Polymer micelles each encapsulating G-CSF were prepared by mixingPEG-pGlu (10-40, 90% C8) and PEG-pGlu (10-40, 25% Chol) at weight ratiosof 19:1, 4:1, and 1:1 in the same manner as in the test example of themixed polymer micelle of Example 3.

The solutions of the polymer micelles each encapsulating G-CSF obtainedabove were administered to male Wistar rats via the tail vein. Thedosage was 100 μg/kg of body weight and the number of animals for thesample was three for each solution. Blood was collected with aheparin-treated syringe from the jugular vein under ether anesthesia 5minutes, 1 hour, 6 hours, 1 day, 2 days, and 3 days after theadministration, and the plasma G-CSF concentration was measured using aG-CSF-ELISA kit (manufactured by RayBiotech, Inc.).

FIG. 4 illustrates the results of Example 4. As seen from FIG. 4, alsoin this example, the retention time of a drug in plasma can becontrolled, in other words, the release speed of a drug can becontrolled by employing a mixed-type micelle. It should be noted that,also in this example, observed values for the plasma G-CSF concentrationwere markedly lower than theoretical values therefor in any of themixed-type micelles.

1. A pharmaceutical composition, comprising: a polymer micellecomposition; and a drug encapsulated in the polymer micelle composition,the drug being one kind selected from the group consisting ofwater-soluble physiologically active polypeptides and proteins eachhaving a molecular weight of 1,500 or more, wherein: the polymer micellecomposition comprises block copolymers each having a hydrophobic polymerchain segment and a hydrophilic polymer chain segment, a plurality ofthe block copolymers being arranged radially in a state in which thehydrophobic polymer chain segment is directed inward and the hydrophilicpolymer chain segment is directed outward; the polymer micellecomposition comprises, as the block copolymers, a block copolymer havingaffinity with HDL and a block copolymer having affinity with alipoprotein excluding HDL; the block copolymer having affinity with HDLhas a hydrophobic polymer chain segment formed of a polyamino acidincluding repeating units derived from a hydrophobic derivative of anamino acid, the hydrophobic derivative of an amino acid including aderivative obtained by introducing a sterol residue into a side chain ofthe amino acid; the block copolymer having affinity with a lipoproteinexcluding HDL has a hydrophobic polymer chain segment formed of apolyamino acid including repeating units derived from a hydrophobicderivative of an amino acid, the hydrophobic derivative of an amino acidincluding a derivative obtained by introducing a hydrophobic grouphaving a linear or branched structure into a side chain of the aminoacid; and detachment of the block copolymer having affinity with HDL isinduced by HDL adhesion attributed to the affinity, a gap formed throughthe detachment causes promotion of release of one kind selected from thegroup consisting of water-soluble physiologically active polypeptidesand proteins each having a molecular weight of 1,500 or more as a drugbeing encapsulated, and the block copolymer having affinity with alipoprotein excluding HDL makes the gap smaller to suppress promotion ofrelease of the drug encapsulated, which allows control of a releasespeed of the drug.
 2. A pharmaceutical composition, comprising: apolymer micelle composition: and a drug encapsulated in the polymermicelle composition, the drug being one kind selected from the groupconsisting of water-soluble physiologically active polypeptides andproteins each having a molecular weight of 1,500 or more, wherein: thepolymer micelle composition comprising comprises block copolymers eachhaving a hydrophobic polymer chain segment and a hydrophilic polymerchain segment, a plurality of the block copolymers being arrangedradially in a state in which the hydrophobic polymer chain segment isdirected inward and the hydrophilic polymer chain segment is directedoutward; the polymer micelle composition comprises a block copolymerhaving affinity with HDL as the block copolymers; the block copolymerhaving affinity with HDL has a hydrophobic polymer chain segment formedof a polyamino acid including repeating units derived from a hydrophobicderivative of an amino acid, the hydrophobic derivative of an amino acidincluding a derivative obtained by introducing a sterol residue into aside chain of the amino acid; the block copolymer having affinity withHDL has a hydrophilic polymer chain segment of poly(ethylene glycol);and detachment of the block copolymer having affinity with HDL isinduced by HDL adhesion attributed to the affinity, a gap formed throughthe detachment causes promotion of release of one kind selected from thegroup consisting of water-soluble physiologically active polypeptidesand proteins each having a molecular weight of 1,500 or more as a drugbeing encapsulated.
 3. The pharmaceutical composition according to claim1, wherein the hydrophobic derivative of an amino acid comprises aderivative of an acidic amino acid selected from aspartic acid andglutamic acid.
 4. (canceled)
 5. The pharmaceutical composition accordingto claims 1, wherein the hydrophobic group having a linear or branchedstructure comprises a C₄ to C₁₈ unsubstituted or substituted linear orbranched alkyl group, a C₄ to C₁₈ unsubstituted or substituted linear orbranched alkenyl group, and a C₄ to C₁₈ unsubstituted or substitutedlinear or branched alkynyl group.
 6. The pharmaceutical compositionaccording to claim 1, wherein the hydrophobic derivative of an aminoacid in the block copolymer having affinity with a lipoprotein excludingHDL comprises a derivative of an acidic amino acid selected fromaspartic acid and glutamic acid.
 7. (canceled)
 8. The pharmaceuticalcomposition according to claim 2, wherein the hydrophobic derivative ofan amino acid comprises a derivative of an acidic amino acid selectedfrom aspartic acid and glutamic acid.
 9. The pharmaceutical compositionaccording to claim 3, wherein the hydrophobic group having a linear orbranched structure comprises a C₄ to C₁₈ unsubstituted or substitutedlinear or branched alkyl group, a C₄ to C₁₈ unsubstituted or substitutedlinear or branched alkenyl group, and a C₄ to C₁₈ unsubstituted orsubstituted linear or branched alkynyl group.
 10. The pharmaceuticalcomposition according to claim 3, wherein the hydrophobic derivative ofan amino acid in the block copolymer having affinity with a lipoproteinexcluding HDL comprises a derivative of an acidic amino acid selectedfrom aspartic acid and glutamic acid.
 11. The pharmaceutical compositionaccording to claim 5, wherein the hydrophobic derivative of an aminoacid in the block copolymer having affinity with a lipoprotein excludingHDL comprises a derivative of an acidic amino acid selected fromaspartic acid and glutamic acid.
 12. The pharmaceutical compositionaccording to claim 9, wherein the hydrophobic derivative of an aminoacid in the block copolymer having affinity with a lipoprotein excludingHDL comprises a derivative of an acidic amino acid selected fromaspartic acid and glutamic acid.